Impaired vascular permeability regulation caused by the VEGF165b splice variant in pre-eclampsia.

Please cite this paper as: Bills V, Salmon A, Harper S, Overton T, Neal C, Jeffery B, Soothill P, Bates D. Impaired vascular permeability regulation caused by the VEGF₁₆₅b splice variant in pre-eclampsia. BJOG 2011; DOI: 10.1111/j.1471-0528.2011.02925.x. Objective Pre-eclampsia is diagnosed by hypertension and proteinuria, probably caused by endothelial dysfunction, resulting in symptoms including oedema, inflammation and altered metabolism. Vascular endothelial growth factor A (VEGF-A) is detected at higher concentrations in plasma from patients with pre-eclampsia than in plasma from normotensive pregnant patients when determined by radioimmunoassay. This study tested the hypothesis that circulating VEGF-A in pre-eclamptic plasma is biologically active in vivo, and aimed to identify specific isoforms responsible for this activity. Design Plasma from pre-eclamptic ( n = 17) and normotensive ( n = 10) pregnant women was perfused into Rana mesenteric microvessels, and the subsequent change in microvascular permeability was measured using a single-vessel perfusion micro-occlusion technique. Results Pre-eclamptic but not normotensive plasma resulted in a 5.25 ± 0.8-fold acute increase in vascular permeability ( P = 0.0003). This increase could be blocked by the incubation of plasma with bevacizumab, an antibody to VEGF-A ( n = 7; P = 0012), and by VEGF-A receptor inhibition by SU5416 at doses specific to VEGF-A receptor-1 (VEGFR1), but not by the VEGF-A receptor-2 inhibitor, ZM323881. Although VEGF₁₆₅b levels were not significantly altered in the PET samples, the increase in permeability was also inhibited by incubation of pre-eclamptic plasma with an inhibitory monoclonal antibody specific for VEGF₁₆₅b ( n = 6; P < 0.01), or by the addition of placental growth factor 1 (PlGF-1; n = 3; P < 0.001). PlGF-1 was detected at lower concentrations in pre-eclamptic plasma than in normotensive plasma. Conclusions These findings suggest that circulating VEGF-A levels in pre-eclampsia are biologically active because of a loss of repression of VEGFR1 signalling by PlGF-1, and VEGF₁₆₅b may be involved in the increased vascular permeability of pre-eclampsia. [ABSTRACT FROM AUTHOR]